No symptoms of heart failing were seen in necropsy)1Heart failing1Global mortality, n (6 of 26: 23%)3210.59 Open in another window AMI indicates acute myocardial infarction; ME, microspheres; TIMI, Thrombolysis In Myocardial Infarction flow grade. *Periprocedural mortality: occurring during or soon ( 6 hours) after the performance of the AMI procedure. Discussion Our investigation provides evidence of an effective, vectorized antagomir therapy that induces favorable postischemic myocardial repair. 5\fold inhibition at 1, 3, and 10 days). Downregulation of miR\92a resulted in significant vessel growth (n=27 adult minipigs randomly allocated to blind receive encapsulated antagomir\92a, Beloranib encapsulated placebo, or saline [n=8, 9, 9]; ValueValueValueValueValueValueValueValueValue /th /thead Periprocedural mortality*, n (4 of 26: 15.4%)2200.35Causes of mortality, nCardiogenic shock due to severe left ventricular dysfunction secondary to thrombus in left main embolized from catheter during TIMI flow analysis at reperfusion1Arrhythmic storm1Retroperitoneal hemorrhage1Bradycardia and asystole1Mortality 30 days after AMI, n (2 of 22: 9.1%)1010.59Causes of mortality, nSudden death (probably arrhythmia. No signs of heart failure were observed in necropsy)1Heart failure1Global mortality, n (6 of 26: 23%)3210.59 Open in a separate window AMI indicates acute myocardial infarction; ME, microspheres; TIMI, Thrombolysis In Myocardial Infarction flow Beloranib grade. *Periprocedural mortality: occurring during or soon ( 6 hours) after the performance of the AMI procedure. Discussion Our investigation provides evidence of an effective, vectorized antagomir therapy that induces favorable postischemic myocardial repair. We have demonstrated that a local intracoronary delivery system based on microencapsulation avoids systemic antagomir\92a biodistribution, allows local, sustained miR\92a inhibition and neovasculogenesis, and prevents adverse ventricular remodeling. Adverse ventricular remodeling is presently still the major cause of contractile dysfunction and heart failure after an AMI.24 Despite advances in pharmacological treatments, reperfusion, resynchronization, and cell therapy, its occurrence has not been abolished.25C33 The thinning and expansion of the infarct area, which results in ventricular dilatation, has been associated with a worsened state of the microcirculation.34C36 Consequently, improving the vascular network by induction of neoangiogenesis has already been proposed as a way to prevent adverse ventricular remodeling.2,37C38 Although benefits have been observed in preclinical experiments with proangiogenic factors, little if any effect has been observed thus far in clinical trials. Antagomir\92a has Mouse monoclonal to GFAP been described to be cardioprotective and to induce neovascularization in small\ and large\animal models, but its beneficial effect against adverse postinfarction remodeling was unknown.13C14 In our study, in a clinically relevant adult minipig model of AMI with transient coronary occlusion and reperfusion, microencapsulated antagomir\92a induced growth of vessels in the infarcted area and led to a significantly reduced occurrence of adverse ventricular remodeling. This model rules out that the observed biological effects are mediated by pathways or stimuli activated only during the growth period of an animal’s life. The underlying mechanism by which induction of Beloranib neoangiogenesis prevents adverse remodeling has been previously investigated. Prevention of cell death of hypertrophied viable myocytes and modification of collagen deposition and scar formation after neoangiogenesis have been demonstrated in a rodent model of myocardial infarction.2 Accordingly, in our study, the scar of treated animals differed qualitatively from that of controls in the collagen composition, with a higher proportion of mature cross\linked collagen I fibers. This higher proportion of collagen I and its multidirectional spatial distribution could determine the major stiffness and mechanical strength of the repair tissue and could have contributed to preventing adverse postinfarct remodeling.39C40 While collagen I and III are the most abundant collagens in Beloranib the reparative scar, recent studies suggest that the nonfibrillar collagens are also deposited during pathological postinfarct healing.41C42 Collagen IV content was detected in the infarct tissue in our study, which could reinforce its role in the organization of the fibrillar collagen network. However, a qualitatively similar proportion of collagen IV deposition was observed in treated and nontreated animals. The influence of the new vessels on cardiac fibroblast activation and fibrillar and nonfibrillar collagen deposition during the healing process requires future investigation. Several obstacles prevent the translation of intravenous injections of antagomir\92a to the prevention of adverse remodeling in clinical practice. Since the polycistronic microRNA 17\92a cluster is ubiquitously expressed, nonselective cell penetration and diffuse miR\92a inhibition in noncardiac organs observed with systemic and regional application may cause unwanted adverse effects at remote locations.14 In addition, to obtain an adequate and sustained concentration in the target cells, antagomir\92a must be repeatedly.